The present invention relates to antitumour 1,5-diazaanthraquinones.
Natural products containing a 9,10-anthracenedione substructure are an important class of antitumour compounds. They include anthracyclines (see a) Lown, J. W. Chem. Soc. Rev. 1993, 22, 165; and b) Sengupta, S. K., in Foye, W. O. (ed.). Cancer Chemotherapeutic Agents, Chapter 5. American Chemical Society, 1995), the pluramycins (see (a) Abe, N.; Enoki, N.; Nakakita, Y.; Uchida, H.; Nakamura, T.; Munekata, M. J. Antibiot. 1993, 46, 1536 and references therein; and b) Hansen, M.; Hurley, L. J. Am. Chem. Soc. 1995, 117, 2421) and some of the enediyne antibiotics (see a) Konishi, M.; Ohkuma, H.; Tsuno, T.; Oki, T.; Van Duyne, G. D.; Clardy, J. J. Am. Chem. Soc. 1990, 112, 3715; and b) Nicolau, K. C.; Dai, W.-M.; Hong, Y. P.; Tsay, S.-C.; Baldridge, K. K.; Siegel, J. S. J. Am. Chem. Soc. 1993, 115, 7944). At least in the case of the anthracyclines, the antitumour activity of these quinones is attributed to formation of DNA damaging anion-radical intermediates by reduction of the quinone unit (see a) Pan, S.-S; Pedersen, L.; Bachur, N. R; Mol. Pharmacol. 1981, 19, 184; and b) Hertzberg, R. P.; Dervan, P. B. Biochemistry 1984, 23, 3934).
Isosteric substitution of one or more carbons of the benzene rings by nitrogen atoms should afford compounds with geometries similar to those of the parent compounds, but with increased affinity for DNA due to the presence of sites suitable for hydrogen bonding or ionic interactions. Also, the electron-withdrawing properties of the heterocyclic rings would facilitate the formation of anion-radicals. For these reasons, the preparation of azaanthraquinones as potential antitumour agents is an active field of research (see Krapcho, A. P.; Maresch, M. J.; Hacker, M. P.; Hazelhurst, L.; Menta, E.; Oliva, A; Spinelli, S.; Beggiolin, G.; Giuliani, F. C.; Pezzoni, G.; Tignella, S. Curr. Med Chem. 1995, 2, 803).
Although the considerations outlined above would apply particularly well to diazaanthraquinones, these compounds have receive little attention (see a) Tapia, R. A., Quintanar, C.; Valderrama, J. A., Heterocycles, 1996, 43, 447; and Brassard, P.; Lxc3xa9vesque, S, Heterocycles, 1994, 38, 2205).
This invention describes a new family of antitumour compounds having the formula (I): 
wherein R3, R4, R7, and R8 are independently selected from the group consisting of hydrogen, lower alkyl, halogen, amine, mono(lower)alkylamine, phenyl, or substituted phenyl. The compounds are new, with the exception of the compound in which R3, R4, R7, R8 are all hydrogen, the compound in which R3 and R7 are hydrogen, R4 is chlorine, and R8 is a 2-nitrophenyl group, the compound in which R3 and R7 are hydrogen, R4 is amino, and R8 is a 2-nitrophenyl group, the comound in which R3, R7 and R8 are hydrogen and R4 is chlorine, and the compound in which R4, R7 and R8 are hydrogen and R3 is methyl.
The present invention also provides a method of treating a mammal affected by a malignant tumour sensitive to a compound with the formula (I), which comprises administering a therapeutically effective amount of a compound with the formula (I), or a pharmaceutical composition thereof.
The present invention further provides pharmaceutical compositions which contain a pharmaceutically acceptable carrier and as active ingredient a compound with the formula (I), as well as a process for its preparation.
The compounds can be made by preparative methods in accordance with this invention.
Preferred Embodiments
In the definitions of the groups R3, R4, R7, and R8 in formula (I), the lower alkyl is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl or hexyl. The substituted phenyl group is preferably substituted with 1 to 4, more preferably 1 or 2 substituents, chosen from lower alkyl, halogen, amine, mono(lower)alkylamine, di(lower)alkylamine, nitro, hydroxy, lower alkoxy, or trifluoromethyl.
Preferred classes of compounds include those of formulae (4), (8), (11), (13), and (14). In these compounds, the substituent groups R3, R4, R7, and R8 are preferably chosen as appropriate from hydrogen, methyl, ethyl, chlorine, dimethylamine, and nitrophenyl.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable formulation of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
The correct dosage of a pharmaceutical composition comprising compounds with the formula (I), will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and tumour being treated. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
In accordance with the preparative methods of this invention, we describe the preparation of five different series of derivatives of the 1,5-diazaanthracene-9,10-dione system, having the formula (I).
Symmetrically substituted derivatives of the 1,5-diazaanthraquinone system (Scheme 1, compounds 4) were prepared by a double hetero Diels-Alder strategy. Thus, 2,5-dibromobenzoquinone (2) was prepared by oxidation of the corresponding hydroquinone (1) with cerium ammonium nitrate (CAN), and treated with 1-dimethylamino-1-azadienes (3) (see Pxc3xa9rez, J. M.; Avendaxc3x1o, C.; Menxc3xa9ndez, J. C., Tetrahedron Lett., 1997, 38, 4717) to give compounds (4): 
As examples of symmetrically substituted derivatives we have prepared: (4a), (4b), (4c), and (4d): 
Unsymmetrically substituted derivatives of the 1,5-diazaanthraquinone system were prepared as shown in Scheme 2. Oxidative demethylation of compounds (5) with cerium ammonium nitrate (CAN) afforded quinones (6), whose treatment with the corresponding 1-dimethylamino-1-azadienes (7) gave the derivatives (8). 
More particularly, as examples of unsymmetrically substituted derivatives, oxidative demethylation of compound (9) (see Waldner, A. Helv. Chim. Acta, 1988, 71, 486) with cerium ammonium nitrate (CAN) afforded quinone (10), whose treatment with 3-substituted 1-dimethylamino-1-azadienes gave directly the aromatized derivatives (11). On the other hand, use of 4-substituted 1-dimethylamino-1-azadienes led to compounds (12), which were aromatized by elimination of dimethylamine under thermal conditions to give compounds (13). Treatment of compounds (12) with dilute HCl led to aromatization with concomitant reaction of dimethylamine with the C-8 position, affording compounds (14): 
As examples of unsymmetrically substituted derivatives we have prepared: (11a), (12a), (13a), (13b), and (14a): 
(13b) was previously described (see Gxc3x3mez-Bengoa, E.; Echavarren, A. M., J Org. Chem., 1991, 56, 3497) by us as an intermediate in the synthesis of pyrido(2,3,4-kl)acridines.
(4a), (4b), (4c), (4d), (11a), (12a), (13a), (13b), and (14a) exhibit antitumour activity. In particular, they exhibits antitumour activity against cell lines derived from human solid tumours, such as human lung carcinoma, human colon carcinoma and human melanoma, and, the like, it is active against other tumour cell lines, like leukemia and lymphoma.
A preferred further aspect of the invention is a method for preparing the compounds (4a), (4b), (4c), (4d), (11a), (12a), (13a), and (14a).